A rate limiting step in the development of therapeutic agents for treating diabetic retinopathy is retinal drug delivery. Although intravitreal injections allow significant drug delivery to the retina, repeated intravitreal injections can lead to endophthalmitis and retinal detachment. Therefore, alternative routes of administration are currently being investigated. Transscleral retinal drug delivery is one such approach. We hypothesized that the eye pigment reduces the extent of transscleral retinal drug delivery in vivo, with the reduction in delivery being greater for drugs with higher melanin binding. Further we hypothesized that diabetes increase transscleral drug delivery to the retina in vivo, due to leakier barriers. The above hypotheses will be assessed at a mechanistic level under two specific aims. Aim 1 will investigate the mechanisms of drug interaction with melanin and determine influence of eye pigmentation on transscleral retinal drug delivery. Aim 2 will correlate leakiness of blood-retinal barriers in diabetic animal models to transscleral retinal drug delivery. This study will investigate widely used model solutes with high and low melanin binding in conjunction with two antiinflammatory agents that are relevant for treating diabetic retinopathy. Both pigmented (Brown Norway) and non-pigmented (Sprague Dawley) rats with and without streptozotocin induced diabetes will be employed in this study. The findings of this study will be useful in developing drugs with enhanced transscleral delivery to the retina in order to treat diabetic retinopathy.